DESCRIPTION: (Principal Investigator's) Polyacetate natural products show a wide variety of significant biological activities. They are of particular interest in the treatment of cancer (bryostatin 1 and spongistatin) and systemic fungal infections (amphotericin B, dermostatin). Many of these natura products have very complex structures that defy any practical synthetic approach. The goal of this proposal is to develop new, practical segment coupling reactions that will facilitate the synthesis of polyacetate natural products. Five new segment coupling reactions are proposed based on 1,3-dioxane-4-one synthons and 4-acetoxy-1,3-dioxane synthons. These synthons will be shown to couple with highly functionalized zinc reagents, allylsilanes, chiral secondar zinc reagents, and Seebach's 1,3-dioxin-4-one synthons. Palladium coupling reactions with enol phosphates derived from 1,3-dioxane-4-ones will also be investigated. These new segment coupling reactions will be developed in the synthesis of four natural products: bryostatin 1, dermostatin B, doliculide an candidin. The methods developed in this grant will set a new standard for efficiency and convergence in the synthesis of highly oxygenated natural products, and will be applicable to the synthesis of other compounds of biological interest.